The kidney has an inherent ability to regenerate following damage. This repair is concomitant with the expression of transcription factor genes such as Pax2 and Lhx1, which are essential for initiating normal kidney organogenesis, suggesting that regenerating tubular cells arise from cells with a primitive, progenitor-like state. Renal progenitors may be formed following the 're-programming' of tubular epithelial cells, such as in mammals, or from cells that permanently reside in the kidney, such as in the adult zebrafish. We hypothesize that any treatment that expands or enhances renal progenitors will accelerate the rate of recovery following acute kidney injury (AKI). To test this we developed larval and adult models of AKI in zebrafish and developed unique tools and methodologies to manipulate renal progenitors. We performed a high-content screen to identify compounds that enhance renal progenitor cell number and identified a novel class of histone deacetylase inhibitors (HDACis) that accelerates renal recovery in zebrafish and mouse models of AKI when given after the induction of injury. The proposed work is divided into three specific aims, which take advantage of the complementary expertise of investigators at two different institutions. Aim 1: We will test whether HDAC inhibition accelerates the rate of recovery following AKI by inducing the proliferation of renal progenitor cells and/or the expression of genes involved in kidney organogenesis. Aim 2: We will determine the importance of Pax2/Pax8 and Lhx1 during normal kidney organogenesis and during the regenerative response by performing loss-of-function and gain-of-function experiments. Aim 3: We wil identify cofactors that comprise the Lhx1 transcriptional complex in order to better understand how this critical factor is involved in activating a kidney program in renal progenitors. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) is a common and largely reversible disorder that has a high mortality but for which there is no specific treatment in humans. Our studies have identified (A) a new class of histone deacetylase inhibitors that accelerate the rate of renal recovery following AKI and (B) a renal progenitor cell population in the adult zebrafish that regenerates damaged kidney tissue. The purpose of our proposed studies is to determine the molecular mechanism by which these agents act to enhance renal regeneration with the ultimate goal of developing new therapies to treat AKI.